EXCEED THE SPACE PROVIDED. The cornerstones for controlling infections caused by non-tuberculosis mycobacteria (NTM) are the macrolides, clarithromycin and azithromycin. The genetic basis of clinically acquired resistance to these agents is conferred by mutation in the 23S ribosomal RNA (rRNA) gene. However, we understand little of the mechanisms of intrinsic macrolide resistance of mycobacteria, particularly M. tuberculosis. Recent studies suggest that mycobacteria have erm methylase genes and macrolide efflux pumps, which may affect suceptibility to macrolides. Therefore, we hypothesize that there are several mechanisms that affect the antimycobacterial activity of macrolides. These mechanisms include drug efflux, expression of erm genes, and, the acquisition of a 23S rRNA gene mutation. Consequently, the long-term objective of this work is to characterize the mutation-independent mechanisms that affect mycobacterial susceptibility to macrolides. To address this objective, this project is divided in to 3 specific aims: (1) to identify the genes conferring inducible macrolide resistance; (2) to investigate the macrolide efflux systems of mycobacteria; and, (3) to characterize the prevalence of resistance genes within the Mycobacteriaceae. Understanding the processes that affect the antimycobacterial activity of macrolides will directly impact the development of new drugs and improve treatment regimens. Of particular interest is improving the anti-tuberculosis activity of macrolides. PERFORMANCE SITE ========================================Section End===========================================

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI052291-03
Application #
6831189
Study Section
Special Emphasis Panel (ZRG1-BM-1 (03))
Program Officer
Sizemore, Christine F
Project Start
2003-07-01
Project End
2006-12-31
Budget Start
2005-01-01
Budget End
2006-12-31
Support Year
3
Fiscal Year
2005
Total Cost
$223,200
Indirect Cost
Name
Children's Hospital of Los Angeles
Department
Type
DUNS #
052277936
City
Los Angeles
State
CA
Country
United States
Zip Code
90027
Andini, Nadya; Nash, Kevin A (2011) Expression of tmRNA in mycobacteria is increased by antimicrobial agents that target the ribosome. FEMS Microbiol Lett 322:172-9
Nash, Kevin A; Brown-Elliott, Barbara A; Wallace Jr, Richard J (2009) A novel gene, erm(41), confers inducible macrolide resistance to clinical isolates of Mycobacterium abscessus but is absent from Mycobacterium chelonae. Antimicrob Agents Chemother 53:1367-76
Nash, Kevin A; Andini, Nadya; Zhang, Yansheng et al. (2006) Intrinsic macrolide resistance in rapidly growing mycobacteria. Antimicrob Agents Chemother 50:3476-8
Andini, Nadya; Nash, Kevin A (2006) Intrinsic macrolide resistance of the Mycobacterium tuberculosis complex is inducible. Antimicrob Agents Chemother 50:2560-2
Nash, Kevin A; Zhang, Yansheng; Brown-Elliott, Barbara A et al. (2005) Molecular basis of intrinsic macrolide resistance in clinical isolates of Mycobacterium fortuitum. J Antimicrob Chemother 55:170-7
Nash, Kevin A (2003) Intrinsic macrolide resistance in Mycobacterium smegmatis is conferred by a novel erm gene, erm(38). Antimicrob Agents Chemother 47:3053-60